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Sunitinib Malate (Sutent) Licensed by Pfizer

Sunitinib Malate (Sutent, SU11248) is a multi-targeted RTK inhibitor targeting VEGFR2 (Flk-1) and PDGFRβ with IC50 of 80 nM and 2 nM, and also inhibits c-Kit.

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Sunitinib Malate (Sutent) Chemical Structure

Sunitinib Malate (Sutent) Chemical Structure
Molecular Weight: 532.56

Validation & Quality Control

Customer Reviews(9)

Quality Control & MSDS

Related Compound Libraries

Sunitinib Malate (Sutent) is available in the following compound libraries:

Cambridge Cancer Compound Library(96-well) Chemical Library (96-well) Chemotherapeutic Agent Library (96-well) FDA Approved Drug Library (96-well) Inhibitor Library (96-well) Kinase Inhibitor Library (96-well) Pfizer Licensed Library Tyrosine Kinase Inhibitor Library (96-Well)

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  • Research Area
  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity Protocol Chemical Information Customer Reviews Product Citations Tech Support & FAQs

Biological Activity

Description Sunitinib Malate (Sutent, SU11248) is a multi-targeted RTK inhibitor targeting VEGFR2 (Flk-1) and PDGFRβ with IC50 of 80 nM and 2 nM, and also inhibits c-Kit.
Targets VEGFR2 (Flk-1) PDGFRβ
IC50 80 nM 2 nM [1]
In vitro Sunitinib also potently inhibits Kit and FLT-3. [1] Sunitinib is a potent ATP-competitive inhibitor of VEGFR2 (Flk1) and PDGFRβ with Ki of 9 nM and 8 nM, respectively, displaying >10-fold higher selectivity for VEGFR2 and PDGFR than FGFR-1, EGFR, Cdk2, Met, IGFR-1, Abl, and src. In serum-starved NIH-3T3 cells expressing VEGFR2 or PDGFRβ, Sunitinib inhibits VEGF-dependent VEGFR2 phosphorylation and PDGF-dependent PDGFRβ phosphorylation with IC50 of 10 nM and 10 nM, respectively. Sunitinib inhibits VEGF-induced proliferation of serum-starved HUVECs with IC50 of 40 nM, and inhibits PDGF-induced proliferation of NIH-3T3 cells overexpressing PDGFRβ or PDGFRα with IC50 of 39 nM and 69 nM, respectively. [2] Sunitinib inhibits phosphorylation of wild-type FLT3, FLT3-ITD, and FLT3-Asp835 with IC50 of 250 nM, 50 nM, and 30 nM, respectively. Sunitinib inhibits the proliferation of MV4;11 and OC1-AML5 cells with IC50 of 8 nM and 14 nM, respectively, and induces apoptosis in a dose-dependent manner. [3]
In vivo Consistent with the substantial and selective inhibition of VEGFR2 or PDGFR phosphorylation and signaling in vivo, Sunitinib (20-80 mg/kg/day) exhibits broad and potent dose-dependent anti-tumor activity against a variety of tumor xenograft models including HT-29, A431, Colo205, H-460, SF763T, C6, A375, or MDA-MB-435. Sunitinib dosing at 80 mg/kg/day for 21 days leads to complete tumor regression in six of eight mice, without tumor re-growing during a 110-day observation period after the end of treatment. Second round of treatment with Sunitinib remains efficacious against tumors that are not fully regressed during the first round of treatment. Sunitinib treatment results in significant decrease in tumor MVD, with ~40% reduction in SF763T glioma tumors. SU11248 treatment results in a complete inhibition of additional tumor growth of luciferase-expressing PC-3M xenografts, despite no reduction in tumor size. [2] Sunitinib treatment (20 mg/kg/day) dramatically suppresses the growth subcutaneous MV4;11 (FLT3-ITD) xenografts and prolongs survival in the FLT3-ITD bone marrow engraftment model. [3]
Clinical Trials A Phase I/II study of Sunitinib in young patients with advanced gastrointestinal stromal tumor is currently ongoing.
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Biochemical Tyrosine Kinase Assays IC50 values for Sunitinib against VEGFR2 (Flk-1) and PDGFRβ are determined using glutathione S-transferasefusion proteins containing the complete cytoplasmic domain of the RTK. Biochemical tyrosine kinase assays to quantitate the trans-phosphorylation activity of VEGFR2 (Flk-1) and PDGFRβ are performed in 96-well microtiter plates precoated (20 μg/well in PBS; incubated overnight at 4 °C) with the peptide substrate poly-Glu,Tyr (4:1). Excess protein binding sites are blocked with the addition of 1-5% (w/v) BSA in PBS. Purified GST-fusion proteins are produced in baculovirus-infected insect cells. GST-VEGFR2 and GST-PDGFRβ are then added to the microtiter wells in 2 × concentration kinase dilution buffer consisting of 100 mM HEPES, 50 mM NaCl, 40 μM NaVO4, and 0.02% (w/v) BSA. The final enzyme concentration for GST-VEGFR2 or GST-PDGFRβ is 50 ng/mL. Twenty-five μL of diluted Sunitinib are subsequently added to each reaction well to produce a range of inhibitor concentrations appropriate for each enzyme. The kinase reaction is initiated by the addition of different concentrations of ATP in a solution of MnCl2 so that the final ATP concentrations spanned the Km for the enzyme, and the final concentration of MnCl2 is 10 mM. The plates are incubated for 5-15 minutes at room temperature before stopping the reaction with the addition of EDTA. The plates are then washed three times with TBST. Rabbit polyclonal antiphosphotyrosine antisera are added to the wells at a 1:10,000 dilution in TBST containing 0.5% (w/v) BSA, 0.025% (w/v) nonfat dry milk, and 100 μM NaVO4 and incubated for 1 hour at 37 °C. The plates are then washed three times with TBST, followed by the addition of goat antirabbit antisera conjugated with horseradish peroxidase (1:10,000 dilution in TBST). The plates are incubated for 1 hour at 37 °C and then washed three times with TBST. The amount of phosphotyrosine in each well is quantitated after the addition of 2,2′-azino-di-[3-ethylbenzthiazoline sulfonate] as substrate.

Cell Assay: [3]

Cell lines RS4;11, MV4;11, and OC1-AML5
Concentrations Dissolved in DMSO, final concentrations ~10 μM
Incubation Time 24 and 48 hours
Method Cells are starved overnight in medium containing 0.1% FBS prior to addition of Sunitinib and FL (50 ng/mL; FLT3-WT cells only). Proliferation is measured after 48 hours of culture using the Alamar Blue assay or trypan blue cell viability assays. Apoptosis is measured 24 hours after Sunitinib addition by Western blotting to detect cleavage of poly (ADP-ribose) polymerase (PARP) or levels of caspase-3.

Animal Study: [2]

Animal Models Female nu/nu mice implanted s.c. with HT-29, A431, Colo205, H-460, SF763T, C6, A375, or MDA-MB-435, and male nu/nu mice bearing luciferase-expressing PC-3M tumors
Formulation Formulated as a carboxymethyl cellulose suspension or as a citrate buffered (pH 3.5) solution
Dosages ~80 mg/kg
Administration Orally once daily
1

References

Chemical Information

Download Sunitinib Malate (Sutent) SDF
Molecular Weight (MW) 532.56
Formula

C22H27FN4O2.C4H6O5
CAS No. 341031-54-7
Synonyms SU-11248
Solubility (25°C)
  • DMSO 15 mg/mL
  • Water <1 mg/mL
  • Ethanol <1 mg/mL
Storage 2 years -20°CPowder
2 weeks4°Cin DMSO
6 months-80°Cin DMSO
Chemical Name (Z)-N-(2-(diethylamino)ethyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide ,(S)-2-hydroxysuccinic acid
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Research Area

Customer Reviews (9)


Click to enlarge 		Rating
Source Varsha Kumar of University of Bern. Sunitinib Malate (Sutent) purchased from Selleck
Method Viral infection
Cell Lines C57BL/6 mice
Concentrations 35 mg/kg
Incubation Time 7 d
Results We performed LCMV infections in the presence of blocking Abs against VEGFR-2 or VEGF-A or in presence of the VEGFR/PDGFR inhibitor sunitinib. In neither case did we observe a significant inhibition of PLN size increase and HEV network expansion on day 8 after infection (Figure C-D)

Click to enlarge 		Rating
Source Surgery, 2012, 152(6), 1045-50. Sunitinib Malate (Sutent) purchased from Selleck
Method Western blot
Cell Lines H295R/SW13 cells
Concentrations 10 nM
Incubation Time 0-48 h
Results Immunoblottting confirmed that sunitinib consistently quashed FLT-3 and RET, 2 of its principaltargets, in a time-dependent manner.

Click to enlarge 		Rating
Source Surgery, 2012, 152(6), 1045-50. Sunitinib Malate (Sutent) purchased from Selleck
Method MTS proliferation assay
Cell Lines H295R/SW13 cells
Concentrations 0-20 nM
Incubation Time 48 h
Results Sunitinib or PD98059 decreases cell proliferation in a dose-dependent manner.

Click to enlarge 		Rating
Source Surgery, 2012, 152(6), 1142-9. Sunitinib Malate (Sutent) purchased from Selleck
Method Western blot
Cell Lines MTC-1.1/TT cells
Concentrations 50 nM
Incubation Time 48 h
Results Sunitinb and sorafenib treatment at the IC50 increased LC3-II protein levels in both MTC-1 .1 and TT cells (Fig A and B). The siRNA-mediated knock-down of Atg- 5, a key molecule for autophagosome formation, abrogated the induction of LC3-II after sunitinib and sorafenib exposure ( Fig C ). These results indicated that both sunitinib and sorafenib promote autophagic activation in MTC cells. Sunitinib and sorafenib exposure also increased the expression level of cleaved caspase-3, a marker of apoptosis, indicating that these TKIs also activate apoptosis.

Click to enlarge 		Rating
Source Surgery, 2012, 152(6), 1142-9. Sunitinib Malate (Sutent) purchased from Selleck
Method MTS cell proliferation assay
Cell Lines MTC-1.1/TT cells
Concentrations 50 nM
Incubation Time 48 h
Results Atg-5 siRNA treatment decreased the antiproliferative effects of sunitinib and sorafenib by 44% ( P < .05) and 41% ( P < .05 ), respectively, in MTC-1 .1 cells and by 43% ( P < .01) and 39% ( P < .05 ), respectively, in TT cells.

Click to enlarge 		Rating
Source Biochem Bioph Res Co , 2010, 398, 205–211. Sunitinib Malate (Sutent) purchased from Selleck
Method Anchorage-independent tumor growth assay, Whole-mount immunofluorescence staining, confocal microscopic imaging
Cell Lines HT-29 human colon cancer cell line
Concentrations 0.1-10 µM
Incubation Time
Results We checked whether sunitinib affects the mass formation of cancer cells. Interestingly, sunitinib inhibited the growth of colony, whereas it did not block the formation of colony. The number of large colonies (>50 µm diameter) was noticeably reduced in the presence of sunitinib, while the number of small colonies (<50 µm diameter) did not differ (Fig. 1A). Under confocal microscopy, hypoxic areas were detected within colonies and HIF-1a was prominently expressed in there(Fig. B, top), whereas small colonies were not hypoxic and scarcely expressed HIF-1a (Fig. B, middle). We next tried to examine whether sunitinib inhibits HIF-1a in the HT-29 colonies. However, as no large colonies were built in the presence of 5 or 10 µM sunitinib, we chose the colonies treated with 1 µM sunitinib, which showed a partial inhibition of colony growth. Consequently, HIF-1a expression was substantially reduced, but still remained, in the colonies positively stained with hypoxyprobe (Fig. 1B, bottom).

Click to enlarge 		Rating
Source Biochem Bioph Res Co , 2010, 398, 205–211. Sunitinib Malate (Sutent) purchased from Selleck
Method Luciferase assay, Western blot
Cell Lines HT-29 cells
Concentrations 0-20 µM
Incubation Time 16/24 h
Results sunitinib suppressed the hypoxic induction of HIF-1 target genes, such as PGK1, PDK1 and CAIX(Fig. B).

Click to enlarge 		Rating
Source Cell Res, 2011, 21, 1080-1087. Sunitinib Malate (Sutent) purchased from Selleck
Method Microangiography
Cell Lines embryos
Concentrations 20 μM
Incubation Time
Results MEK1/2 may cooperate with VEGFR to regulate blood vessel lumen diameter. We examined this hypothesis by combining VEGFR inhibitor Sunitinib and MEK1/2 inhibitor U0126. Indeed, U0126 (10 µM) combined with Sunitinib (20 µM) resulted in a reduction of vessel lumen size (Figure F), whereas individually they did not. Combined treatment of another MAP kinase signaling pathway inhibitor Dasatinib(20 µM) with Sunitinib(20 µM) produced a similar phenotype as PP1, whereas each individual inhibitor did not result in any vessel shrinkage even at much higher concentrations ( Figure 5C). Since there are three major VEGF receptors, it is desirable to determine which receptor is involved in combinatory action with MEK1/2. To address this issue, additional highly selectiveVEGFR inhibitors PTK787 and ZM323881 were tested. Both of these inhibitors (PTK787 or ZM323881), when individually combined with Dasatinib or U0126, induced a reduction of vessel lumen size (Figure D, E, G, and H).

Click to enlarge 		Rating
Source Biochem Bioph Res Co , 2010, 398, 205–211. Sunitinib Malate (Sutent) purchased from Selleck
Method Luciferase assay, Western blot
Cell Lines HT-29 cells
Concentrations 0-40 μM
Incubation Time 8/16 h
Results To determine which translational pathway is regulated by sunitinib, we used two reporter plasmids, namely, Tk/5' -UTR-Luc reporter designed for cap-dependent translation and CMV/GFP-5'-UTR-Luc reporter for IRES-dependent translation. Both reporter activities were found to be dose-dependently reduced by sunitinib (Fig. A and B). Since AKT signaling is known to regulate HIF-1a translation, we measured the cellular levels of phospho-AKTs as indices for AKT activation, and found that sunitinib reduced AKT phosphorylation at Thr308 and Ser473 residues (Fig. C). These results suggest that sunitinib reduces HIF-1α 5'-UTR-driven translations by inhibiting AKT or its upstreams.

Product Citations (11)

  • Peroxiredoxin 1 Controls Prostate Cancer Growth through Toll-Like Receptor 4-Dependent Regulation of Tumor Vasculature. [Riddell JR, et al. Cancer Res 2011;71(5):1637-46]

    PubMed: 21343392

  • von Hippel-Lindau tumor suppressor mutants faithfully model pathological hypoxia-driven angiogenesis and vascular retinopathies in zebrafish. [van Rooijen E, et al. Dis Model Mech 2010;3(5-6):343-53]

    PubMed: 20335444

  • Autophagic activation potentiates the antiproliferative effects of tyrosine kinase inhibitors in medullary thyroid cancer. [Lin CI, et al. Surgery 2012;152(6):1142-9]

    PubMed: 23158184

  • Strategic combination therapy overcomes tyrosine kinase coactivation in adrenocortical carcinoma. [Lin CI, et al. Surgery 2012;152(6):1045-50]

    PubMed: 23102636

  • Development and Validation of a High-Throughput Intrinsic ATPase Activity Assay for the Discovery of MEKK2 Inhibitors. [Ahmad S, et al. J Biomol Screen 2012;ahead of print]

    PubMed: 23134735

  • Detection of Allosteric Kinase Inhibitors by Displacement of Active Site Probes. [Lebakken CS, et al. J Biomol Screen 2012;17(6):813-21]

    PubMed: 22453235

  • Sunitinib deregulates tumor adaptation to hypoxia by inhibiting HIF-1a synthesis in HT-29 colon cancer cells. [Shin HW, et al. Biochem Bioph Res Co 2010;398(2), 205-211]

    PubMed: 20599738

  • The heat shock protein 90 inhibitor IPI-504 induces KIT degradation, tumor shrinkage, and cell proliferation arrest in xenograft models of gastrointestinal stromal tumors. [Floris G, et al. Mol Cancer Ther 2011;10(10), 1897-1908]

    PubMed: 21825009

  • PDGF signalling controls age-dependent proliferation in pancreatic b-cells. [Chen H, et al. Nature 2011;478(7369), 349-355]

    PubMed: 21993628

  • Combinatory action of VEGFR2 and MAP kinase pathways maintains endothelial-cell integrity. [Zhong H, et al. Cell Res 2011;21(7), 1080-1087]

    PubMed: 21423276

  • Global lymphoid tissue remodeling during a viral infection is orchestrated by a B cell-lymphotoxin-dependent pathway. [Kumar V, et al. Blood 2010;115(23), 4725-4733]

    PubMed: 20185585

Tech Support & FAQs

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